Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Chemical analysis
Reexamination Certificate
2002-12-16
2004-11-09
Nghiem, Michael (Department: 2863)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Chemical analysis
C702S045000
Reexamination Certificate
active
06816793
ABSTRACT:
TECHNICAL FIELD
The present invention generally relates to powder flow testing and analysis. More specifically, the present invention relates to a method for predicting the flow properties of powders based on a ranking of data derived from one or more powder flow tests.
BACKGROUND ART
In many processes or systems involving powder materials, especially pharmaceutical manufacturing processes, the material being processed must possess good flow properties in order for the manufacturing process to be successful. In the case of pharmaceutical processes, the material generally constitutes a formulation or blend of active ingredients as well as excipients. The excipients are usually inert substances (e.g., gum arabic, starch and the like) which serve as a vehicle for the active ingredients, or as lubricants, glidants, and bulking components. Poor flow characteristics of such formulations can result in equipment stoppages, clogged outlets, flooded compartments, and other conditions that disrupt the flow of the material during processing. One example of an important pharmaceutical process in which good flow properties are critical is the compression of powders into tablets that require uniform, consistent dosages and compositions. Powder compression can involve known process steps such as funneling, avalanching, tumbling, plug drop and the like.
The widespread use of powders in the pharmaceutical industry has given rise to a variety of methods for characterizing powder flow. Much research has been directed toward attempting to correlate the various measures of powder flow to manufacturing properties. It is believed that the multitude of test methods developed thus far is a result of the fact that powder flow behavior is multifaceted and complex. The pharmaceutical scientist often utilizes one or more of the standard tests to assess the flowability potential of sample powder materials and formulations. For a given manufacturing process and a given active drug substance or compound, such tests are employed to evaluate the optimal blend of active ingredients and excipients constituting the bulk quantity to be processed. It is well documented that the various flow tests generally accepted and commonly employed to date often do not correlate well with observed behavior on a development or production scale. One reason is that none of the tests reflect an intrinsic property of the powder being tested. In other words, each test is strongly dependent upon its respective methodology. There is a growing awareness, therefore, that because powder flow in general is a complex phenomenon, no single, simple test method can adequately characterize the wide range of flow properties observed for pharmaceutical powders.
Examples of basic, conventional flow tests are as follows. One popular test is the static angle of repose test. This test measures the “angle of repose,” which can be defined as the constant, three-dimensional angle relative to a horizontal base that is assumed by a cone-like pile of material formed by any of several different methods. A lower angle of repose value indicates better powder flow. The angle of repose is formed by permitting powder to drop through a funnel onto a fixed, vibration-free base that includes a retaining lip to retain a layer of powder on the base. The height of the funnel is varied during the test in order to carefully build up a symmetrical cone of powder. Typically, the funnel height is maintained approximately 2 to 4 cm from the top of the powder pile as it is being formed in order to minimize the impact of falling powder on the tip of the cone. Alternatively, the funnel could be kept fixed while the base is permitted to vary as the pile forms. The angle of repose is determined by measuring the height of the powder cone and calculating the angle of repose ∀ from the following equation:
tan
(
α
)
=
height
1
/
2
base
One variation of this test is the drained angle of repose test, wherein an excess quantity of material positioned above a fixed diameter base is allowed to “drain” from the container. The drained angle of repose is determined from the cone of powder formed on the base. Another variation is the dynamic angle of repose test, in which a cylinder is filled and rotated at a specified speed. The dynamic angle of repose is the angle formed by the flowing powder.
It is believed that the angle of repose is essentially a measure of interparticulate friction, or resistance to movement between particles. Experimental difficulties arise in the use of this test due to segregation of material and consolidation or aeration of the powder as the cone is formed. Also, the peak of the cone of powder can be distorted by the impact of the powder falling from above, although this can be minimized somewhat by carefully building up the cone. In addition, the design of the base upon which the cone is formed influences the angle of repose. The provision of a fixed diameter base having a protruding outer edge can ameliorate this latter influence by ensuring that the cone of powder is formed on a retained layer of powder. Of course, if a powder of a given formulation is not capable of forming a symmetrical cone, this test is entirely inappropriate. Thus, although widely accepted as being valuable in predicting manufacturing problems, the angle of repose test has nonetheless been criticized on the grounds of lack of reproducibility and inconsistency in its ability to correlate with manufacturing properties or other measures of powder flow.
Another popular test for predicting powder flow characteristics measures the compressibility index or the closely related Hausner ratio. The test involves measuring the bulk or aerated density V
a
of a powder in a graduated cylinder, placing the cylinder on a tap density tester such as a Vanderkamp TAP DENSITY TESTER™, and measuring the “tapped” density V
f
of the powder, i.e., the density of the powder after tapping the cylinder a number of times (e.g., 200) until no further volumetric changes occur. A lower compressibility index value indicates better powder flow. One of the following calculations is then made:
compressibility
index
=
100
×
(
V
a
-
V
f
V
a
)
Hausner
ratio
=
V
a
V
f
The values obtained as a result of this test are believed to be measures of the cohesiveness of a powder as it forms an arch in a hopper and the ease with which such an arch could be broken. In one variation, the rate of consolidation is also, or alternatively, measured. Factors influencing the methods used to obtain the compressibility index and the Hausner ratio include the diameter of the cylinder used, the number of times the powder is tapped to achieve the tapped density, the mass of material used in the test, and rotation of the sample during tapping.
Another type of test entails monitoring the rate of flow and/or change in flow rate of a powdered material through an orifice in order to obtain a measure of flowability and an indication of the effects of glidants, granule size and type of granulating agent on powder flow. The “flow through the orifice” test is useful only for free-flowing, non-cohesive materials. Either mass flow rate or volumetric flow rate can be measured, and done so either continuously or discretely. It is generally recommended that the container employed for this test be a vibration-free cylinder with a circular orifice. The size and shape of the container and orifice are important experimental variables. The diameter of the cylinder is recommended to be greater that two times the diameter of the orifice, while the diameter of the orifice is recommended to be greater than six times the diameter of the particles to be tested. A hopper could also serve as the container where representative of flow in a manufacturing situation. A funnel is not recommended since its stem would affect the flow rate. The test might involve the use of empirical equations that relate flow rate to the orifice diameter, particle size, and particle density.
A diverse array of shear cell m
Chow Kwok Yui
Lockhart Danielle Marie
Tallevi Andrew Giuseppi Guido
Nghiem Michael
Smith Robert J.
SmithKline Beecham Corportion
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